Open Access
ACS Infectious Diseases, volume 5, issue 4, pages 570-581
Mechanistic and Structural Basis for the Actions of the Antibacterial Gepotidacin against Staphylococcus aureus Gyrase
1
Medicines Discovery Institute, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, United Kingdom
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2
Infectious Diseases Discovery, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States
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3
VA Tennessee Valley Healthcare System, 1310 24th Avenue S., Nashville, Tennessee 37212, United States
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Publication type: Journal Article
Publication date: 2019-02-13
Journal:
ACS Infectious Diseases
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 5.3
ISSN: 23738227
PubMed ID:
30757898
Infectious Diseases
Abstract
Gepotidacin is a first-in-class triazaacenaphthylene novel bacterial topoisomerase inhibitor (NBTI). The compound has successfully completed phase II trials for the treatment of acute bacterial skin/skin structure infections and for the treatment of uncomplicated urogenital gonorrhea. It also displays robust in vitro activity against a range of wild-type and fluoroquinolone-resistant bacteria. Due to the clinical promise of gepotidacin, a detailed understanding of its interactions with its antibacterial targets is essential. Thus, we characterized the mechanism of action of gepotidacin against Staphylococcus aureus gyrase. Gepotidacin was a potent inhibitor of gyrase-catalyzed DNA supercoiling (IC50 ≈ 0.047 μM) and relaxation of positively supercoiled substrates (IC50 ≈ 0.6 μM). Unlike fluoroquinolones, which induce primarily double-stranded DNA breaks, gepotidacin induced high levels of gyrase-mediated single-stranded breaks. No double-stranded breaks were observed even at high gepotidacin concentration, long cleavage times, or in the presence of ATP. Moreover, gepotidacin suppressed the formation of double-stranded breaks. Gepotidacin formed gyrase-DNA cleavage complexes that were stable for >4 h. In vitro competition suggests that gyrase binding by gepotidacin and fluoroquinolones are mutually exclusive. Finally, we determined crystal structures of gepotidacin with the S. aureus gyrase core fusion truncate with nicked (2.31 Å resolution) or intact (uncleaved) DNA (2.37 Å resolution). In both cases, a single gepotidacin molecule was bound midway between the two scissile DNA bonds and in a pocket between the two GyrA subunits. A comparison of the two structures demonstrates conformational flexibility within the central linker of gepotidacin, which may contribute to the activity of the compound.
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Gibson E. G. et al. Mechanistic and Structural Basis for the Actions of the Antibacterial Gepotidacin against Staphylococcus aureus Gyrase // ACS Infectious Diseases. 2019. Vol. 5. No. 4. pp. 570-581.
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Gibson E. G., Bax B., CHAN P. F., Osheroff N. Mechanistic and Structural Basis for the Actions of the Antibacterial Gepotidacin against Staphylococcus aureus Gyrase // ACS Infectious Diseases. 2019. Vol. 5. No. 4. pp. 570-581.
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TY - JOUR
DO - 10.1021/acsinfecdis.8b00315
UR - https://doi.org/10.1021%2Facsinfecdis.8b00315
TI - Mechanistic and Structural Basis for the Actions of the Antibacterial Gepotidacin against Staphylococcus aureus Gyrase
T2 - ACS Infectious Diseases
AU - CHAN, PAN F.
AU - Gibson, Elizabeth G
AU - Bax, B.
AU - Osheroff, Neil
PY - 2019
DA - 2019/02/13 00:00:00
PB - American Chemical Society (ACS)
SP - 570-581
IS - 4
VL - 5
PMID - 30757898
SN - 2373-8227
ER -
Cite this
BibTex
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@article{2019_Gibson,
author = {PAN F. CHAN and Elizabeth G Gibson and B. Bax and Neil Osheroff},
title = {Mechanistic and Structural Basis for the Actions of the Antibacterial Gepotidacin against Staphylococcus aureus Gyrase},
journal = {ACS Infectious Diseases},
year = {2019},
volume = {5},
publisher = {American Chemical Society (ACS)},
month = {feb},
url = {https://doi.org/10.1021%2Facsinfecdis.8b00315},
number = {4},
pages = {570--581},
doi = {10.1021/acsinfecdis.8b00315}
}
Cite this
MLA
Copy
Gibson, Elizabeth G., et al. “Mechanistic and Structural Basis for the Actions of the Antibacterial Gepotidacin against Staphylococcus aureus Gyrase.” ACS Infectious Diseases, vol. 5, no. 4, Feb. 2019, pp. 570-581. https://doi.org/10.1021%2Facsinfecdis.8b00315.